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Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes α4β2 and α7

Bisson, William ; Westera, Gerrit ; Schubiger, P. ; Scapozza, Leonardo

In: Journal of Molecular Modeling, 2008, vol. 14, no. 10, p. 891-899

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    Titel
    • Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes α4β2 and α7
    Autor
    • Bisson, William. Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen and University Hospital of Zürich, Swiss Federal Institute of Technology Zurich, Ramistrasse 100, 8091, Zurich, Switzerland
    • Westera, Gerrit. Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen and University Hospital of Zürich, Swiss Federal Institute of Technology Zurich, Ramistrasse 100, 8091, Zurich, Switzerland
    • Schubiger, P.. Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen and University Hospital of Zürich, Swiss Federal Institute of Technology Zurich, Ramistrasse 100, 8091, Zurich, Switzerland
    • Scapozza, Leonardo. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, 24 rue du General-Dufour, 1211, Geneva, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Journal of Molecular Modeling, 2008, vol. 14, no. 10, p. 891-899. Springer-Verlag
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:320508
    Summary
    In recent years, it has become clear that the neuronal nicotinic acetylcholine receptor (nAChR) is a valid target in the treatment of a variety of diseases, including Alzheimer's disease, anxiety, and nicotine addiction. As with most membrane proteins, information on the three-dimensional (3D) structure of nAChR is limited to data from electron microscopy, at a resolution that makes the application of structure-based design approaches to develop specific ligands difficult. Based on a high-resolution crystal structure of AChBP, homology models of the extracellular domain of the neuronal rat and human nAChR subtypes α4β2 and α7 (the subtypes most abundant in brain) were built, and their stability assessed with molecular dynamics (MD). All models built showed conformational stability over time, confirming the quality of the starting 3D model. Lipophilicity and electrostatic potential studies performed on the rat and human α4β2 and α7 nicotinic models were compared to AChBP, revealing the importance of the hydrophobic aromatic pocket and the critical role of the α-subunit Trp—the homolog of AChBP-Trp 143—for ligand binding. The models presented provide a valuable framework for the structure-based design of specific α4β2 nAChR subtype ligands aimed at improving therapeutic and diagnostic applications. Figure Electrostatic surface potential of the binding site cavity of the neuronal nicotinic acetylcholine receptor (nAChR). Nicotinic models performed with the MOLCAD program: a rat α7, b rat α4β2, c human α7, d human α4β2. All residues labeled are part of the α7 (a,c) or α4 (b,d) subunit with the exception of Phe 117, which belongs to subunit β2 (d). Violet Very negative, blue negative, yellow neutral, red very positive